What we already know about this topic

Short-acting inhaled beta-agonists (SABA), together with steroids and oxygen, are the mainstay of the treatment of acute asthma exacerbations in adult patients (1, 2). Among others therapeutic strategies, guidelines advice to consider the association of SABA with short-acting anti-cholinergics (SAAC) in patients with moderate-severe exacerbations (grade of recommendation 1++ for SIGN guidelines (2) and level of evidence A in GINA guidelines (1)). The biological rationale of this approach lies in the possibility of exploiting the faster and stronger bronchodilators effects of SABA coupled with the longer lasting, even if weaker, effects of SAAC, which act on different receptors and ensure also a reduction in airways secretions.

Previous systematic reviews failed to demonstrate any advantage in reduction of hospitalization (RR 0,80, IC 95% 0,61 - 1,06) of the combined SABA and SAAC therapy (3). The authors of the work we are going to talk about in this commentary aim to re-evaluate clinical efficacy of the association of SABA and SAAC association vs. SABA alone for the same outcome, taking into account of more recent evidence.

Quality of included studies: only one study was considered to be at low risk of bias. There was high or unclear risk of bias in all the methodological domains evaluated. No publication bias about the main outcome was detected using funnel plots.

Comment and conclusions

According to the results of this meta-analysis, combination therapy is more effective than SABA therapy alone in reducing hospital admissions in adult asthma patients; subgroup analysis has shown that this clinical efficacy is maintained in mild, moderate, and severe exacerbations. Adverse events appear to be more frequent with SABA and SAAC association therapy than with SABA therapy alone. Side effects reported were dry mouth, tremor, anxiety, agitation, palpitations, nausea, headache, and blurred vision; no differences in prevalence for any specific side effect was detected, probably because of insufficient study power.

Overall, this study has significant limitations. First of all, considered studies are small, with only eight including more the 100 and three more than 200 patients (Fitzgerald 1997, Garrett 1997, Karpel 1996). One previous systematic review (3), including only these three works (which individually failed to demonstrate significant differences between study arms regarding the main outcome), didn’t detect a reduction in hospitalization (RR 0,80, IC 95% 0,61 - 1,06). Small studies in meta-analyses are usually more heterogeneous (5), of lesser quality (6), and tend to overestimate clinical effect (7). The concerns about the low overall quality of the evidence are strengthened by the observation that the single study with low risk of bias (Cydulka 2000) didn’t show any difference in term of efficacy of the combined inhaled therapy.

The acceptable balance of combined therapy between reported clinical efficacy and adverse effects is counterbalanced by the relevant risk of bias of the included studies, which makes it hard to draw any meaningful conclusion. For these reasons, this systematic review doesn’t seem to support any change in the approach recommended by current guidelines, which limit its use to severe cases.